Noninvasive molecular imaging and targeted drug delivery systems, often referred to as theranostic agents, are being developed to enable improved detection, patient risk stratification and site-specific treatment. There is a need in the art for the development of theranostic agents that may be used with a wide variety of imaging techniques, such as x-ray, CT, spectral CT (K-edge imaging), ultrasound, magnetic resonance, positron emission tomography, optical and photoacoustic tomographic imaging.
Spectral CT Imaging
Conventional CT uses x-rays to generate tomographical images of the x-ray absorption from the object under investigation. The dominating physical absorption effects are the so-called photoelectric effect and the Compton Effect. Both effects depend on the atomic number of the elements, the mass density and the energy. Biological tissue consists mostly of a mixture of elements with low atomic numbers. Only calcium has a somewhat larger atomic number and density. The contrast of CT is therefore dominated by the relative large contrast between air, soft tissue and bone (or other calcified objects). Different soft tissue types show only a limited contrast, which is usually directly coupled to density differences. CT contrast agents are based on dense elements with a high atomic number such as iodine. Earlier attempts to utilize the energy dependency of the absorption to improve the contrast in CT were technically successful but showed only limited clinical value. These so-called dual-energy techniques utilize the element dependent difference between the two dominating absorption effects to provide additional contrasts.
The measurement techniques of dual-energy CT provide only low energy resolution. This limitation can be overcome with advanced detector technology that provides good spectral resolution. Such detectors are based on photon counting devices with energy discrimination. Instead of just measuring the deposed energy of the entire x-ray beam, as it is done in conventional detectors, each individual photon is detected and its energy is measured. Spectral CT can improve the absorption contrast in CT to its physical limitations. Although better than conventional CT the added clinical value of spectral CT is limited, because the elementary composition of biological tissue does not yield strong differences in x-ray absorption.
This situation changes dramatically if spectral CT is used in combination with K-edge imaging. The photoelectric absorption contains some strong resonance effects at certain energies. If an x-ray photon contains enough energy to excite an electron in the K-shell, the absorption increases dramatically. The K-edge energy depends on the atomic number of the element. Some elements such as gadolinium, gold or bismuth have their K-edge in the x-ray energy band of CT. The spectral footprint of these elements combined with spectral CT detector technology provides unique imaging features. The high energy resolution of photon counting detectors and proper mathematical processing methods allow a complete separation of the attenuation from the K-edge material and the remaining elements. Spectral CT K-edge imaging can be seen as two simultaneous acquisitions where one is only sensitive to the K-edge material and the other is only conventional CT. Both imaging tasks (combined in a single real scan) provide separate images. The K-edge image shows only the K-edge material similar to PET or SPECT imaging where only the isotopes are visible. The other image shows a conventional CT image just without the K-edge material. It has been proven that the K-edge images deliver quantitative information of the K-edge material concentration.
Photo Acoustic Tomography
Photoacoustic tomography is a nonionizing imaging modality based upon differential absorption of electromagnetic waves for different tissue types. This imaging technique has attracted the attention of biomedical engineers for non invasive imaging. Photo Acoustic Tomography (PAT) is a materials analysis technique based on the reconstruction of an internal photoacoustic source distribution from measurements acquired by scanning ultrasound detectors over a surface that encloses the source under study. The PA source is produced inside the object by the thermal expansion that results from a small temperature rise, which is caused by the absorption of externally applied radiation of pulsed electromagnetic (EM) waves. This technique has great potential for applications in the biomedical field because of the advantages of ultrasonic resolution in combination with EM absorption contrast. PAT is also called optoacoustic tomography (OAT) or thermoacoustic tomography (TAT), with the term “thermoacoustic” emphasizing the thermal expansion mechanism in the PA generation. OAT refers particularly to light-induced PAT, while TAT is used to refer to rf-induced PAT.
Myocardial Infarction
Myocardial infarction is the leading cause of death for both men and women all over the world. As many as 200,000 to 300,000 people in the United States die each year before medical help is sought. Approximately 1.3 million cases of nonfatal myocardial infarction are reported for an annual incidence of approximately 600 per 100,000 people. Strikingly, around 300,000 Americans die from heart attacks each year before they reach a hospital. The proximate cause of myocardial infarction is coronary plaque rupture with thrombotic occlusion of blood supply.
Since the early work of Benson and Constantinides the acute formation of thrombus following atherosclerotic plaque rupture has been well recognized as the etiology of unstable angina, myocardial infarction, transient ischemic attacks and stroke. Although a myriad of medical advances in the detection and treatment of severe carotid and coronary artery stenosis have emerged, the most common source of thromboembolism remains rupturing vulnerable plaques that reside in vessels with only 50 to 60% residual stenosis. Sensitive detection and differentiation of vulnerable versus stable atherosclerotic plaques in vessels with mild severity stenosis remains limited with angiography, regardless of modality. Luminal imaging provides minimal information about arterial intimal pathology, and compensatory arterial remodeling to preserve lumen dimensions within diseased vessels further disguises the severity of atherosclerotic plaque burden.
A variety of approaches have emerged to detect vulnerable plaques based on intravascular ultrasound elastography, radionuclide imaging, and thermography, but magnetic resonance imaging (MRI) has emerged as a particularly sensitive modality to noninvasively visualize thromboses within the carotid artery. Unfortunately, wide excursions of the coronary vasculature during the cardiac cycle complicate routine MR coronary angiography and currently preclude MR molecular imaging of micro thrombus in the intimal microfissures of unstable plaque.
Multislice CT has emerged as the modality of choice for noninvasive coronary angiography (CTA). Current 16 and 64 slice scanners can generate contrast enhanced angiograms in 25 ms or less, and the eventual development of up to 256 slice scanners will permit complete acquisitions within one heart cycle. Although CTA, like MRA, is best for ruling out significant coronary disease, one expects that improved resolution of vascular detail will parallel faster data acquisitions and reduced blurring from partial volume dilution and motion artifacts. Yet, coronary calcium, a prominent feature of advanced atherosclerotic plaques and aging coronary vessels, will continue to present lumen assessment difficulties typically in suspect regions. Moreover, rapid multislice imaging will not detect intimal micro fissuring, and attenuation CT contrast agents, even if homed to thrombus features, will not be easily resolved from mural calcium deposits. Hence, there is a need in the art for improved imaging agents.